Our studies in the CS Project continue our identification of genetic determinants of chemotherapeutic sensitivity of agents that target CRC and ALL. In the ALL Project we obtain primary malignant cells for determining in vitro drug sensitivity and identifying genes associated with drug resistance in primary cancer tissue (46). This is not practical . for CRC. Our second approach for the CS project is to test for inherited determinants of drug sensitivity using LCLs derived from CEPH families. Three-generation pedigrees provide the power to evaluate the genetic contribution to anticancer drug cytotoxicity (41). Drugs that are relevant to the objectives of PAAR include: etoposide (ALL, CRC, CYP3A);vincristine and daunbrubicin (ALL, CYP3A);mercaptopurine and cytarabine (ALL);SN-38 and platinating agents (CRC). Complementary studies are being performed in CREATE (42) and we are working together to share baseline microarray data, genotyping on CEPH cell lines and statistical expertise (see letter from Dr. McLeod). We hypothesize that a significant component of cellular susceptibility to cytotoxic agents is due to heritable factors.